Symptomatic knee osteoarthritis (OA) affects 10% of men and 13% of women 60 years or older, and depressive symptoms are common, estimated to be prevalent in one-fifth of these patients. Depressive symptoms worsen knee OA disease severity and are a barrier to pain management and engagement in physical activity. Clinical care guidelines recommend depression treatment in older adults with knee OA but provide no direction on how to simultaneously manage both conditions, and patients are often not treated for their depressive symptoms and receive interventions only for their chronic physical illness. This issue is exacerbated by the routine exclusion of individuals with chronic physical diseases and comorbid depression from clinical trials and lack of protocols designed for these patients. Recent research advocates the use of treatments that benefit both conditions simultaneously, or combined treatment using two interventions in parallel that are designed to work together, such that approaches enhance efficacy beyond that of an individual therapy with a single disease target. Treatment guidelines advise exercise programs to manage pain and disability and improve psychosocial health in those with knee OA, but compliance to physical activity protocols is low in persons with chronic pain and disability and is only made worse by comorbid depression. Adherence is critical to the efficacy of depression treatments using exercise training, and no such exercise program has ever been designed for and tested in OA patients with co-occurring depressive symptoms in a way to enhance compliance. Duloxetine is the only antidepressant medication indicated for pain management in knee OA patients that has demonstrated efficacy and tolerability when treating depression in older adults, and therefore, is a viable pharmacological complement to exercise training. There are no protocols that combine treatments using interventions that affect symptoms of both knee OA and depression, and a strategy focused on co- management of the two conditions could be disseminated to and implemented by generalist medical practitioners. Thus, the research goal of this K01 application is to evaluate the feasibility of and then pilot test a protocol comprised of aerobic exercise training plus duloxetine for the treatment of symptomatic knee OA and comorbid depression. The proposed research will be implemented with a period of close mentoring and career development activities focused on learning 1) methods for qualitative data collection and analysis that can be used to understand patients? perspectives and experiences and 2) strategies for the implementation and evaluation of interventions in clinical research. This proposal is aligned with the NIA Strategic Directions for Research on Aging emphasizing older adults with multiple chronic conditions that complicate clinical care and is intended to lead to a research program that uses observational epidemiology evaluating the relationships and mechanisms between musculoskeletal disorders and comorbid depression in older adults to inform the development of protocols that are designed to manage symptoms of both the primary condition and sequalae.